Olaf S. Andersen, M.D.

Professor of Physiology and Biophysics

  • Director, Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program


1300 York Avenue, Room C-501 B
New York, NY 10065

Research Areas

Research Summary:

  • Energetic coupling between membrane proteins and their host lipid bilayer
  • Bilayer-mediated effects of biologically active molecules
  • Bilayer-dependent basis for cytotoxicity

Membrane protein function varies with changes in the composition (and physical properties) of the bilayer in which the protein is embedded, and the bilayer properties may change not only in response to changes in lipid composition but also in response to drug partitioning into the bilayer. This regulation of protein function involves both specific interactions between the protein and individual molecules (drugs or lipids) in the bilayer, and more general interactions between the protein and the lipid bilayer as a liquid crystal with physical properties (thickness, intrinsic curvature and the associated elastic moduli).

This is important for two interrelated reasons.  First, because the physico-chemical properties known to befall efficacious compounds — sufficient aqueous and lipid solubility — means that many, if not most, drugs are amphiphiles that partition into the bilayer/solution interface and thereby alter the bilayer’s physical properties.  Second, because integral membrane proteins (e.g., receptors, channels and transporters) undergo conformational changes that involve the proteins’ bilayer-spanning domains, which are coupled to the bilayer core through hydrophobic interactions. The bilayer adaptation to a membrane protein’s hydrophobic domain, the protein-induced bilayer deformation, has an energetic cost \(\left( \Delta G_{def}\right)\) that varies with changes in protein shape and bilayer properties. The free energy difference of a conformational change between protein states I and II \(\left( \Delta G^{I\rightarrow II}_{total}\right)\) thus will be the sum of contributions from rearrangements within the protein \(\left( \Delta G^{I\rightarrow II}_{protein}\right)\) and within the bilayer \(\left( \Delta G^{I\rightarrow II}_{bilayer} = \Delta G^{II}_{def} – \Delta G^{I}_{def}\right)\). For integral membrane proteins, with their irregular protein/bilayer boundary, there will be an additional contribution from the inevitable residual exposure of hydrophobic and polar residues \(\left( \Delta G^{I\rightarrow II}_{res} = \Delta G^{II}_{res} – \Delta G^{I}_{res}\right)\).

An extensive literature has demonstrated the regulation of cell and membrane protein function by changes in lipid bilayer composition. This bilayer-mediated regulation of membrane protein function is important because changes in lipid bilayer properties, e.g. due to the partitioning of drugs into the bilayer/solution interface, will alter the \(\Delta G^{I\rightarrow II}_{bilayer}\) and \(\Delta G^{I\rightarrow II}_{res}\)  contributions to \(\Delta G^{I\rightarrow II}_{total}\), providing a mechanism for the changes in protein function.  When such drug-induced changes in the bilayer contributions to \(\Delta G^{I\rightarrow II}_{total}\) become sufficiently large they produce global effects and, eventually, cytotoxicity.

Current experiments address the following questions:

  • What are the relation(s) between molecular structure and bilayer-modifying potency; can we predict the changes in bilayer properties (expressed as \(\Delta G^{I\rightarrow II}_{total}\)) based on a drug’s structure?
  • What are the biological consequences of drugs bilayer-modifying effects; at what point do they become cytotoxic; can we predict if a drug candidate is likely to have undesired effects?
  • What are bilayer-modifying effects of small peptides and proteins?
  • Can we develop experimental strategies for distinguishing between specific and bilayer-mediated regulation of membrane protein function?

Recent Publications:

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